The aim of this project is to investigate the role of serine, cysteine and metallo-proteases in the development and progression of mouse epithelial cancers and to test the effects of anti-protease therapy in inhibiting these processes. Transgenic models for the development and progression of mouse tumors will be used to characterize the nature of protease involvement in transformation of epithelial cells as well as primary tumor growth. Invasion and metastasis. By crossing these animals into mouse backgrounds that are null for specific proteases or protease inhibitors, or that overexpress specific protease inhibitors on constitutive or temporally regulated promoter/enhancers, it will be possible to determine when specific proteases or classes of proteases act, and which processes (growth, invasion, metastasis, genomic instability) are downstream from protease action. The relative contributions of proteases from epithelial and/or stromal sources will be evaluated by transplanting neoplastic tissue or cells from one type of protease background onto animals of a distinct background. Angiogenesis, stromal activation and tumor development will then be assessed. Taken together, these model systems will elucidate the role of proteases in the development of the preneoplastic lesions as well as in malignant conversion, and provide proof-of- concept for anti-protease therapy in different stages of the development and progression of epithelial cancers.